Functional disomy of Xp including duplication of DAX1 gene with sex reversal due to t(X;Y)(p21.2;p11.3)

Abstract

Translocations involving the short arms of the X and Y in human chromosomes are uncommon. One of the best-known consequences of such exchanges is sex reversal in 46,XX males and some 46,XY females, due to exchange in the paternal germline of terminal portions of Xp and Yp, including the SRY gene. Translocations of Xp segments to the Y chromosome result in functional disomy of the X chromosome with an abnormal phenotype and sex reversal if the DSS locus, mapped in Xp21, is present. We describe a 7-month-old girl with severe psychomotor retardation, minor anomalies, malformations, and female external genitalia. Cytogenetic analysis showed a 46,X,mar karyotype. The marker was identified as a der(Y)t(Xp;Yp) by fluorescence in situ hybridisation analysis. Further studies with specific locus probes of X and Y chromosomes made it possible to clarify the break points and demonstrated the presence of two copies of the DAX1 gene, one on the normal X chromosome and one on the der(Y). The karyotype of the child was: 46,X,der(Y)t(X;Y)(p21.2;p11.3). The syndrome resulted from functional disomy Xp21.2-pter, with sex reversal related to the presence of two active copies of the DAX1 gene located in Xp21. Few cases of Xp disomy with sex reversal have been reported, primarily related to Xp duplications with 46,XY karyotype, and less often to Xp;Yq translocations. To our knowledge, our patient with sex reversal and a t(Xp;Yp) is the second reported case.

Case Report Molecular characterisation of a der(Y)t(Xp;Yp) with Xp functional disomy and sex reversal

“…Sex reversal due to Xp21 disomy is rare and has been observed as a result of an interstitial duplication of Xp21, an X;A translocation or an X;Y translocation (Sanlaville et al, 2004;Barbaro et al, 2007Barbaro et al, , 2008Tzschach et al, 2008). The patient reported here is one of a small number of reported cases resulting from an X;Y translocation (Table 3), and the only one that has been resolved at the level of oligonucleotide-based CMA.…”

“…46,X,der(Y)t(X;Y)(p21.2;p11.3) Female external genitalia, developmental delay/mental retardation, hypotonia, dysmorphic facial features, Sanlaville et al, 2004 no identifiable gonads by ultrasound, growth retardation, partial agenesis of the corpus callosum.…”

A Cytogenomic Approach in a Case of Syndromic XY Gonadal Dysgenesis

“…In addition, the AMH pattern of expression is related to SF1 and WT1 , which are also modulated by DAX1 [Ledig et al, 2010]. Overexpression of DAX1 also represses INSL3 and testosterone in Leydig cells which are involved in testis descent, Wolffian stabilization and external genital virilization [Sanlaville et al, 2004;Zarate et al, 2011;Sukumaran et al, 2013]. Our patient has well-developed Müllerian ducts, but no evidence of gonads (even atrophic), Wolffian derivatives and external genital virilization.…”

“…Some patients with DSD reported before the development of microarray technologies had a complex phenotype including dysmorphic features and/or intellectual disability [Sanlaville et al, 2004] generally caused by large chromosome rearrangements detected by conventional karyotyping. This approach was helpful to identify genes involved in testes development [Baumstark et al, 1996;Ledig et al, 2010].…”

The Genetics of Disorders of Sex Development in Humans

“…Duplications of DAX1 have been shown to cause 46,XY DSD [Baumstark et al, 1996;Sanlaville et al, 2004]. While loss-of-function mutations or deletions of the DAX1 gene result in patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism, no effect on testicular development was observed [Muscatelli et al, 1994].…”